It is well established that brief periods of ischemia, i.e. ischemic preconditioning (IPC) offers powerful self-protection of the myocardium from subsequent ischemia/reperfusion injury. However, recent evidence indicate that IPC is severely compromised in humans and animals with advanced age, which group is most likely to suffer from acute angina/myocardial infarct. The mechanisms of this age-related defect is not well understood. Further more, new pharmacological interventions mimicking IPC which offer effective myocardial protection for the aging heart are not yet available. For this pilot project, our specific aims are a, to investigate the cellular mechanisms of age-related defects in ischemic preconditioning; b. to explore whether brief exposure to volatile anesthetic sevoflurane, i.e. anesthetic preconditioning (APC), offers myocardial protection for the aged heart from ischemia-reperfusion injury. Isolated perfused hearts from young (6 months old) and senescent (28 months old) Fisher 344 rats will be subjected to IPC or APC followed by ischemia and reperfusion. Cytosolic and mitochondrial Ca2+ (detected by Indo-1) and mitochondria metabolism (NADH fluorescence) in left ventricles will be monitored real time with fiber optic probes. Myocardial protection will be evaluated by infarct size, integrity of sarcoplasmic reticulum, mitochondria, myofilaments, sarcolemma, and cytoskeleton using western blots. The specific role of mitochondrial KATP channels and small heat shock proteins in myocardial protection will be explored. These parameters will provide a systematic view of the age-related defect in IPC and show whether APC can effectively protect the aging heart. The long term objectives of this project, as a new research area for this laboratory, are to investigate new interventions which may protect the aged myocardium from ischemia/reperfusion injury.